14-3-3 is implicated in cell survival, proliferation, migration, and tumor growth; however, its clinical relevance in tumor progression and metastasis have never been elucidated. To evaluate the clinical significance of 14-3-3, we analyzed the association of 14-3-3 expression and clinicopathologic characteristics in primary and subsequent metastatic tumors of hepatocellular carcinoma patients. 14-3-3 was expressed abundantly in 40 of 55 (70.7%) primary tumors. Increased 14-3-3 expression in primary tumors predicted a higher 5-year cumulative incidence of subsequent extrahepatic metastasis, and multivariate analysis revealed 14-3-3 overexpression was an independent risk factor for extrahepatic metastasis. Patients with increased 14-3-3 expression in primary tumors had worse 5-year overall survival rates, and 14-3-3 overexpression was an independent prognostic factor on Cox regression analysis. Furthermore, stably overexpressed 14-3-3 enhanced hepatocellular carcinoma cell migration and proliferation and increased anchorage-independent cell growth. In addition, in vivo study in a nude-mice model showed tumor formation significantly increased with 14-3-3 overexpression. In conclusion, this is the first report to show that increased 14-3-3 expression is associated with subsequent extrahepatic metastasis and worse survival rates, as well as cancer progression of hepatocellular carcinoma. Thus, 14-3-3 may be a novel prognostic biomarker and therapeutic target in hepatocellular carcinoma.
Background: Caveolin-1 assists in COX-2 degradation through the proteasome pathway. Results: Caveolin-1 enhances interactions among COX-2, Derlin-1, and the p97-Ufd1 complex and assists in COX-2 retrotranslocation and ubiquitination. Conclusion: Caveolin-1 is a cofactor facilitating COX-2 degradation via a Derlin-1-p97 pathway. Significance: Results represent a novel model for Derlin-1-mediated N-glycosylated protein degradation facilitated by caveolin-1.
Acute hepatic injury caused by inflammatory liver disease is associated with high mortality. This study examined the role of caveolin‐1 (Cav‐1) in lipopolysaccharide (LPS) and D‐galactosamine (GalN)‐induced fulminant hepatic injury in wild type and Cav‐1‐null (Cav‐1−/−) mice. Hepatic Cav‐1 expression was induced post‐LPS/GalN treatment in wild‐type mice. LPS/GalN‐treated Cav‐1−/− mice showed reduced lethality and markedly attenuated liver damage, neutrophil infiltration and hepatocyte apoptosis as compared to wild‐type mice. Cav‐1 deletion significantly reduced LPS/GalN‐induced caspase‐3, caspase‐8 and caspase‐9 activation and pro‐inflammatory cytokine and chemokine expression. Additionally, Cav‐1−/− mice showed suppressed expression of Toll‐like receptor 4 (TLR4) and CD14 in Kupffer cells and reduced expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 in liver cells. Cav‐1 deletion impeded LPS/GalN‐induced inducible nitric oxide synthase expression and nitric oxide production and hindered nuclear factor‐κB (NF‐κB) activation. Taken together, Cav‐1 regulated the expression of mediators that govern LPS‐induced inflammatory signalling in mouse liver. Thus, deletion of Cav‐1 suppressed the inflammatory response mediated by the LPS‐CD14‐TLR4‐NF‐κb pathway and alleviated acute liver injury in mice.
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